This study aimed to assess the effectiveness of repeated subgingival instrumentation combined with 980 nm diode laser decontamination in the non-surgical treatment of deep periodontal pockets. A total of 40 otherwise healthy patients with generalized periodontitis, encompassing 1,168 sites with deep pockets, were included and baseline PPD, bleeding on probing (BOP), gingival recession (REC), clinical attachment level (CAL), and plaque index (PI) were recorded. Each patient underwent non-surgical laser-assisted periodontal therapy and was enrolled in a maintenance program with three-month recall visits during the first year of follow-up. In non-responding sites, site-specific non-surgical instrumentation was repeated during follow-up visits. The achievement of pocket closure (PPD ≤ 4 mm with negative BOP) was evaluated as the primary outcome. Changes in the above parameters were also measured at 3 months (T1) and 1 year (T2). Additionally, a logistic regression model was constructed to explore the association of pocket closure at T2 with several predictor variables. At the three-month evaluation, 677 of the treated sites (57.96%) achieved pocket closure. This number increased significantly after one year, with 977 out of 1,168 sites (83.65%) requiring no further treatment. The logistic regression analysis indicated that a higher number of roots, older age, history of diabetes mellitus, and greater baseline PPD were associated with lower pocket closure at T2. Within its limitations, the present study demonstrates that the outcomes of initial non-surgical periodontal therapy can be further enhanced by repeated site-specific laser assisted non-surgical instrumentation, scheduled quarterly during the first year of follow-up.